Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

• Published in: Journal of medicinal chemistry 2016-07, Vol.59 (13), p.6265-6280
• Main Authors: Lajarín-Cuesta, Rocío, Nanclares, Carmen, Arranz-Tagarro, Juan-Alberto, González-Lafuente, Laura, Arribas, Raquel L, Araujo de Brito, Monique, Gandía, Luis, de los Ríos, Cristóbal
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00478

We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer’s disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca2+ channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatases, which have been marginally aimed, even despite their key role in protein τ dephosphorylation. Twenty-five compounds were synthesized, and mostly their neuroprotective profile exceeded that offered by the head compound gramine. In general, these compounds reduced the entry of Ca2+ through VGCC, as measured by Fluo-4/AM and patch clamp techniques, and protected in Ca2+ overload-induced models of neurotoxicity, like glutamate or veratridine exposures. Furthermore, we hypothesize that these compounds decrease τ hyperphosphorylation based on the maintenance of the Ser/Thr phosphatase activity and their neuroprotection against the damage caused by okadaic acid. Hence, we propose this multitarget approach as a new and promising strategy for the treatment of neurodegenerative diseases.